The Section of Orthopaedic Surgery and Rehabilitation is actively involved in clinical and translational research, including: gene therapy approaches to bone and musculoskeletal disorders; analysis of polyethylene wear in joint replacements and the biology of osteolysis; biological intervention of polyethylene wear particle-induced osteolysis; and flatfoot deformity contact characteristics.

Gene Therapy Approaches To Bone And Musculoskeletal Disorders

Articular Cartilage Regeneration

Drs. Sherwin Ho, Michael Terry and Bruce Reider have been investigating the biological processes in articular cartilage regeneration and anterior cruciate ligament repair.  Articular cartilage has little intrinsic capacity to repair itself after injury, prompting many researchers to explore new methods to facilitate and augment cartilage regeneration.  Currently, a variety of approaches have been developed, including: chondroplasty, osteochondral transfer procedures (autologous and allograft procedure), microfracture and autologous cultured chondrocyte implant (ACCI).  Each technique is useful when utilized in appropriate conditions. However, a significant cohort of patients still fail to achieve good to excellent results even when surgical, pharmacological and physical therapy are optimal. These clinical failures suggest that new biologic strategies, including gene therapy, may be a useful adjunct to current treatments to further improve clinical outcome. 

Drs. Ho, Terry and Reider are investigating the use of Sox9 and/or other biofactors to facilitate articular cartilage regeneration. Previously, Drs. T.-C. He and Rex Haydon successfully transduced intervertebral disc cells with Sox9, a transcription factor necessary for chondrogenesis and Type II collagen synthesis. They observed that human degenerative intervertebral disc cells transfected with Sox9 genes led to chondrocyte proliferation with increased production of Type II collagen. Currently, Drs. Ho, Terry and Reider are investigating whether ex vivo expression of Sox9 in articular cartilage cells or in mesenchymal stem cells will augment articular cartilage repair in a rabbit model. Dr. Ho received the AOSSM Young Investigator Award to carry out the Sox9 gene therapy investigation.  Drs. Ho and Terry are also investigating the potential use of BMP-13 and/or other biological factors in augmenting Anterior Cruciate Ligament (ACL) repair in a rabbit model.

Gene Therapy in Flexor Tendon Healing

Dr. Daniel Mass, in collaboration with Drs. T.-C. He, Rex C. Haydon and Hue H. Luu, is investigating gene therapy approaches to enhance tendon and ligament healing using recombinant adenoviral vectors expressing BMP-13 and/or other biological factors. In a recent study, which was funded by the Orthopaedic Research and Education Foundation (OREF), Dr. Mass and colleagues demonstrated that BMP-13 can significantly improve the biomechanical properties of lacerated flexor tendons in a rabbit model. More comprehensive studies of gene therapy in flexor tendon healing are underway.

Gene Therapy in Spinal Fusion

Dr. Purnendu Gupta has been investigating the different fixation techniques for multilevel anterior cervical discectomy and fusion (ACDF).  ACDF is a common surgical procedure used to treat radiculopathy or myelopathy in the cervical spine.  However, there are multiple fixation methods used to promote cervical fusion.  Dr. Gupta has examined static versus dynamic plating techniques for multilevel ACDF and has presented his results at the Annual Meetings of the North American Spine Society and the American Academy of Orthopaedic Surgeons.  In addition, Dr. Gupta has been involved in collaborative investigations examining a percutaneously-inserted pedicle screw-rod system following anterior lumbar arthrodesis as well as functional impairment and the prediction of spine loading.

The direction of spine research at the University of Chicago has also included the application of gene therapy in spinal fusion. In collaboration with Dr. Purnendu Gupta, Drs. T.-C. He, Rex C. Haydon, and Hue H. Luu have completed an animal study to demonstrate an ex vivo gene therapy approach to posterior-lateral spinal fusion using BMP-2, BMP-6, and BMP-9. The findings were presented at the Annual Meetings of the North American Spine Society and the Orthopaedic Research Society.  These studies have been supported by research grants from the North American Spine Society and the Musculoskeletal Transplant Foundation.

Analysis Of Polyethylene Wear In Joint Replacements And The Biology Of Osteolysis

As director of the Orthopaedic Biomedical Imaging Institute, Dr. John Martell has completed an extensive evaluation of two- and three-dimensional techniques for the analysis of polyethylene wear in total hip replacements. Dr. Martell's research has been funded by research grants from NIH/NIAMS  and DePuy/J & J.  The Orthopaedic Biomedical Imaging Institute is becoming known nationally and internationally as a resource for the design and implementation of polyethylene wear studies and has been involved in the analysis of cross-linked polyethylene from Zimmer, DePuy/J & J, Stryker/Howmedica/Osteonics and Richards.  Dr. Martell is now getting requests from visitors to observe the techniques used in processing and analyzing films.  Together with Dr. David Manning, Dr. Martell intends to develop the Orthopaedic Biomedical Imaging Institute into a world-class resource for the analysis of polyethylene wear in total hip and total knee arthroplasty. 

Dr. Martell has recently developed several important and innovative biomedical imaging tools. First, his mechanical analysis software allows investigators to calculate the joint reaction force and stress in normal and prosthetic hips.  Using the joint stress as a predictor variable in combination with patient activity indicators (speed of walking, UCLA score or pedometer data) he has developed a multiple logistic regression model that can identify patients with total hips that will have high wear and lysis in the long term. This model is now 87 percent accurate and has no false negatives in a series of 300 hips with a minimum 8 year follow-up. Dr. Martell is investigating the use of stress levels in native hips to identify patients who will progress to hip arthritis. Second, Dr. Martell developed pre-op templating software that allows surgeons to see the predicted stress on the hip joint and identifies reconstructive options that will put the patient at risk for high wear. This software would show in real-time the best combination of implant size and position to minimize wear. Third, Dr. Martell is working in collaboration with Dr. Maryellen Giger in the Kurt Rossman Laboratory to develop radiographic texture analysis techniques for the early detection of pelvic osteolysis in patients with total hip replacements. Preliminary data shows that texture analysis detects changes in peri-acetabular bone two years prior to the development of clinically apparent osteolysis on X-rays. Finally, Dr. Martell has upgraded his leg length discrepancy program for application in the pediatric clinic by Dr. Christopher Sullivan. 

Dr. Henry Finn continues his work in the development of new prosthetic devices for both primary and revision total hip replacement.  The Vanguard Rx Condular Constrained Knee will be available as a standard product line device in Spring 2005.  In addition, he has developed a new antiprotruseo cage for revision acetabuli and is currently working on a femoral component specific for minimal invasive hip surgery.

Biological Intervention of Polyethylene Wear Particle-Induced Osteolysis

Dr. David Manning is interested in developing more effective therapeutic and/or preventive measures for the clinical management of osteolysis, the most common complication of total joint prostheses that is estimated to occur in over 25 percent of implant recipients. Dr. Manning has recently completed an in vivo wear comparison study of highly crosslinked and traditional polyethylene in total hip arthroplasty.  Current strategies to combat osteolysis include modifications of the bearing surface to decrease particle generation and biologic and/or pharmaceutical treatments once osteolysis has occurred.  Alternate bearings, as of yet, have not proven to be effective.  Pharmaceutical applications of bisphosphonates, fosamax and anti-inflammatories have also been unsuccessful. 

In collaboration with Drs. T.-C. He and Rex C. Haydon, Drs. Manning and Hue H. Luu are investigating the potential use of several osteogenic BMPs (e.g., BMP-2, BMP-6, and BMP-9) as a biologic treatment of osteolysis-related bone loss.  Successful non-operative treatment of osteolysis would improve implant survival, prevent many revision arthroplasties, and simplify revision reconstruction techniques. Recently, Dr. Manning has been granted the Louis Block Award and Maley Research Award to study the treatment of wear particle-induced osteolysis with the osteogenic BMPs in rodent models.

Flatfoot Deformity Contact Characteristics

Dr. Brian Toolan, in collaboration with Dr. Louis Draganich, has completed the development of a cadaveric model on the effects of acquired flatfoot deformity on tibiotalar contact characteristics and is currently applying this model to investigate corrective procedures with orthotics.  As an extension of this investigation, he has completed a study examining the effects of UCBL orthotics on joint contact characteristics in our adult acquired flatfoot deformity model.  This manuscript has been submitted to Foot and Ankle International for publication.  Similarly, Drs. Toolan and Draganich have begun a parallel study to investigate the effects of orthotics on gait and stair stepping in patients with flatfoot deformity. 

In addition to his interests in flatfoot deformity, Dr. Toolan is interested in developing a better understanding of ruptured Achilles tendon healing process and developing new therapies.  Achilles tendon ruptures are common injuries and both surgical and non-surgical treatments have frequent complications such as wound dehiscence and re-rupture.  Therefore, Dr. Toolan, in collaboration with Drs. He, Haydon and Luu, is developing a rat model to investigate the effects of BMP13 and other factors on Achilles tendon healing.  This study has been funded by a research grant to Dr. Toolan from the American Orthopaedic Foot & Ankle Society.